Bottom Line:
Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism.We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes.Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain.

Background: Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes.

Objectives: The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters.

Methods: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system.

Results: Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density.

pone-0007281-g004: Intrauterine position affects adult bone and vascular metabolism.(A) Bar graph of the area-under-curve (intolerance surface) from the figure 3C, D. (B) Bone mass density according to the intrauterine position in LP and HP mice. (C) Influence of the intrauterine position on blood pressure in LP and HP mice. Black bars represent HP animals while empty bars symbolize LP animals. Red curves represent the GTT performed on animals fed on a LP diet, and those from HP mice are shown with blue curves. Results are mean±SEM (n = 3-10), *p<0.05, **p<0.01, ***p<0.001 between the linked groups.

Mentions:
Interestingly, we found that IUP affects the glycemic control of adults from both the HP and LP groups (p = 0.0284) (Figure 3C, D). Glucose intolerance was higher in 2M LP mice when compared to 2F LP mice, suggesting that either fetal enrichment with androgens decreases glycemic control or that higher estrogen levels (here by two female embryos) improves glucose homeostasis. Phytoestrogens are considered as pseudo-agonists, since their activity depends on the level of natural estrogens. For instance, their activity is low at physiological levels of estrogen (1 nM), such as those found in pre-menopausal women, and it rises when levels of estradiol are lower (0.01 nM), such as those found in post-menopausal women [24]. Consistent with these pseudo-agonistic properties of isoflavones in presence of estrogens, exposure to phytoestrogens radically improved the glucose intolerance found in 2M males, while it had no influence in 2F males (see Figure 4A, which is an area under curve of Figure 3C, D). These findings suggest that the IUP affects glucose tolerance and that minute changes in estrogenic compounds can potentially trigger important changes in adult glucose tolerance.

pone-0007281-g004: Intrauterine position affects adult bone and vascular metabolism.(A) Bar graph of the area-under-curve (intolerance surface) from the figure 3C, D. (B) Bone mass density according to the intrauterine position in LP and HP mice. (C) Influence of the intrauterine position on blood pressure in LP and HP mice. Black bars represent HP animals while empty bars symbolize LP animals. Red curves represent the GTT performed on animals fed on a LP diet, and those from HP mice are shown with blue curves. Results are mean±SEM (n = 3-10), *p<0.05, **p<0.01, ***p<0.001 between the linked groups.

Mentions:
Interestingly, we found that IUP affects the glycemic control of adults from both the HP and LP groups (p = 0.0284) (Figure 3C, D). Glucose intolerance was higher in 2M LP mice when compared to 2F LP mice, suggesting that either fetal enrichment with androgens decreases glycemic control or that higher estrogen levels (here by two female embryos) improves glucose homeostasis. Phytoestrogens are considered as pseudo-agonists, since their activity depends on the level of natural estrogens. For instance, their activity is low at physiological levels of estrogen (1 nM), such as those found in pre-menopausal women, and it rises when levels of estradiol are lower (0.01 nM), such as those found in post-menopausal women [24]. Consistent with these pseudo-agonistic properties of isoflavones in presence of estrogens, exposure to phytoestrogens radically improved the glucose intolerance found in 2M males, while it had no influence in 2F males (see Figure 4A, which is an area under curve of Figure 3C, D). These findings suggest that the IUP affects glucose tolerance and that minute changes in estrogenic compounds can potentially trigger important changes in adult glucose tolerance.

Bottom Line:
Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism.We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes.Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain.

Background: Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes.

Objectives: The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters.

Methods: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system.

Results: Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density.